How should I evaluate and manage a patient presenting with low‑grade fever and an enlarged inguinal lymph node?

Evaluation and Management of Low-Grade Fever with Inguinal Lymphadenopathy

Begin with fine-needle aspiration (FNA) of the enlarged inguinal lymph node if it is palpable, as this has 91.7% sensitivity and 98.2% specificity for detecting malignancy and should be performed before empiric antibiotics in most cases. 1, 2

Initial Clinical Assessment

Your physical examination must systematically evaluate specific anatomical regions to identify the source:

• Inspect the ipsilateral lower extremity for cuts, abrasions, insect bites, cellulitis, or fungal infections between the toes, as these are common causes of reactive inguinal lymphadenopathy 3
• Examine the perineal, genital, and perianal regions for lesions, ulcers, trauma, or dermatologic conditions that could explain the lymphadenitis 3
• Document node characteristics: palpability, number, unilateral vs. bilateral presentation, dimensions, mobility vs. fixation, relationship to surrounding structures (skin, Cooper ligaments), and presence of edema in penis, scrotum, or legs 4, 1
• Assess for constitutional symptoms: night sweats, weight loss, and duration of fever, as these suggest malignancy or systemic infection 5, 6

Critical Differential Diagnoses

The differential is broad but can be systematically narrowed:

Malignant Causes (30-50% of palpable nodes are inflammatory, but malignancy must be excluded first) 1, 2

• Penile or vulvar squamous cell carcinoma: The most common malignancy draining to inguinal nodes 4
• Melanoma of the lower extremity 2
• Lymphoma: Can present with fever, night sweats, and generalized lymphadenopathy including inguinal nodes 5, 6
• Metastatic disease from pelvic malignancies 4

Infectious Causes

• Cat-scratch disease (Bartonella henselae): Presents with inguinal lymphadenopathy, low-grade fever, and night sweats; may form sinuses and ulcers 7
• Sexually transmitted infections: Consider lymphogranuloma venereum (LGV), HSV, or syphilis only if genital lesions are present or patient is sexually active 3, 2
• Infectious mononucleosis (EBV): Can cause generalized lymphadenopathy including inguinal nodes with fever; check for lymphocytosis >50% with atypical morphology 8
• Skin/soft tissue infections: Reactive lymphadenopathy from lower extremity cellulitis or fungal infections 2

Inflammatory/Rheumatologic Causes

• Indolent lymphoproliferative disorders: Rare but can present as fever of unknown origin with inguinal lymphadenopathy 6

Diagnostic Algorithm

Step 1: Immediate Laboratory Evaluation

• Complete blood count with differential: Look for lymphocytosis (>50% suggests EBV), atypical lymphocytes, or leukocytosis 8
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP): Elevated levels warrant advanced imaging if initial workup is unrevealing 9
• Blood cultures if fever is persistent 9

Step 2: Tissue Diagnosis (DO NOT DELAY)

• Fine-needle aspiration (FNA) is mandatory for any palpable inguinal lymph node with fever, as it has 91.7% sensitivity and 98.2% specificity for malignancy 1, 2
• If FNA is negative but clinical suspicion remains high (heterogeneous appearance on imaging, persistent fever, constitutional symptoms), proceed immediately to excisional biopsy 1, 2
• If FNA is positive for malignancy, proceed directly to oncologic management without delay 2
• Consider metagenomic sequencing if infectious etiology is suspected but cultures are negative, particularly for fastidious organisms like Bartonella 7

Step 3: Imaging (Based on Initial Findings)

• CT or MRI of pelvis and abdomen if nodes are palpable, to assess size, extent, relationship to structures, and presence of pelvic/retroperitoneal nodes 4
• 18F-FDG PET/CT if ESR/CRP are elevated and diagnosis remains unclear after initial evaluation, as this has high accuracy for detecting occult malignancy and distant metastases 4, 9
• Chest imaging to evaluate for mediastinal lymphadenopathy if lymphoma is suspected 5

Management Based on Etiology

If Malignancy is Confirmed

• Immediate inguinal lymph node dissection (ILND) for penile or vulvar cancer with positive nodes 1, 2
• Disease-specific oncologic protocols for lymphoma or metastatic disease 2

If Infectious Etiology is Identified

• Bartonella henselae (cat-scratch disease): Azithromycin per Sanford Guide; may require surgical debridement if sinus formation occurs 7
• EBV/infectious mononucleosis: Supportive care; antibiotics should be omitted 8
• Bacterial skin/soft tissue infection: Treat underlying infection and monitor node regression 2

If Reactive/Inflammatory Lymphadenopathy

• Address underlying cause (treat skin infection, fungal infection, etc.) 1
• Schedule clinical reassessment in 2-4 weeks; nodes should decrease in size within 4-6 weeks 3
• If no improvement at 4-6 weeks, reconsider diagnosis and escalate to excisional biopsy 3

Critical Pitfalls to Avoid

• Do NOT assume all palpable lymphadenopathy is malignant, as 30-50% of cases are inflammatory, but you must prove this with FNA 1, 2
• Do NOT proceed to immediate surgical excision without FNA first, as this causes unnecessary morbidity and delays diagnosis 2
• Do NOT start empiric antibiotics without tissue diagnosis unless the patient is neutropenic, immunocompromised, or critically ill, as this obscures the diagnosis and has not been shown to be effective for fever of unknown origin 9
• Do NOT delay biopsy if fever persists beyond 3 weeks (fever of unknown origin definition), as up to 75% of cases resolve spontaneously but the remainder require tissue diagnosis 9
• Do NOT misinterpret lymphoid hyperplasia on imaging as lymphoma without tissue confirmation; infectious mononucleosis causes generalized lymphadenopathy that can mimic malignancy 8

Follow-Up Strategy

• If confirmed reactive lymphadenopathy: Monitor node size and characteristics at 2-4 week intervals; consider repeat biopsy if nodes enlarge or fail to regress by 4-6 weeks 3, 1
• If malignancy is confirmed: Follow disease-specific oncologic protocols with repeat imaging to assess treatment response 1, 2
• If diagnosis remains elusive after comprehensive workup: Consider referral to tertiary center for multidisciplinary consultation and advanced diagnostics including metagenomic sequencing 7